5-amino derivatives of 4-thiazolidinones and process therefor



United States Patent C) 3,072,653 S-AMINO DERIVATIVES OF4-THIAZOLIDINONES AND PROCESS THEREFOR Gerhard Satzinger, Memingen,Allgau, Germany, as-

signor to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., acorporation of Delaware No Drawing. Filed Mar. 6, 1961, Ser. No. 93,32012 Claims. (Cl. 260247.1)

The present invention relates to new and novel S-amino derivatives of4-thiazolidinones of the formula:

wherein R is hydrogen, lower alkyl or aryl, R is carbalkoxy in which thealkyl portion is lower alkyl, R is lower alkyl and R is di-loweralkylamino or a cyclic amino radical selected from the group consistingof piperidino, morpholino, pyrrolidino or mono-lower alkyl derivativesthereof. The present invention also relates to a new and novel method ofpreparing the above compounds and to new and novel intermediatesobtained in the synthesis.

The term lower alkyl as used throughout the specification and in theclaims refers to branched and straight chain aliphatic groups having 1to 6 carbon atoms.

The new and novel S-amino derivatives of 4-thiazolidinones of thisinvention have been found to have interesting pharmacological activityas analgesic, sedative, choleretic and diuretic agents. In use, they maybe formulated with conventional pharmaceutical carriers to form suchtypical dosage units as tablets, capsules, solutions, suspensions,suppositories and the like.

It has now been found that the new and novel S-amino derivatives of4-thiazolidinones of this invention of the formula:

wherein R R R and R are as described hereinabove may be prepared by thefollowing reaction sequence.

First, a substituted 4-thiazolidinone of the formula:

is treated with bromineto form the corresponding bromo derivative of theformula:

The reaction is carried out at normal room temperatures, for exampleabout 25 C., in a suitable inert solvent such as chloroform. The bromineis preferably added slowly to the starting material as a solution in aninert solvent, for example chloroform. The S-bromo derivative isrecovered by evaporation of the solvent and may be purified bycrystallization.

The S-bromo compound is then converted to the new 3,072,653 PatentedJan. 8, 1963 Useful amines included within the scope of the formula R Hare dimethylamine, diethylamine, dibutylamine, piperidine, morpholine,pyrrolidine, 2-methylpiperidine, 2-ethylpiperidine, 3-ethylmorpholine,2-methylmorpholine, S-methylmorpholine, 3-butylpyrrolidine,2-methylpyrrolidine and the like. The reaction is normally carried outat room temperature in an appropriate inert solvent for the reactants,for example benzene, toluene and the like, with the preferred molarratio of the reactants being 2 moles of the amine to 1 mole of theS-bromo derivative. During the course of the reaction, the hydrobromidesalt of the amine separates and is removed by filtration. The filtrateis then evaporated and the residue purified by crystallization. Thefinal product may, if desired, be converted to a non-toxic acid additionsalt, for example the hydrochloride, by treatment with an appropriateacid.

The starting materials for the preparation of the new and novelcompounds of this invention, which starting materials have the formula:

may be prepared as follows.

First, a substituted 4-thiazolidinone of the formula:

wherein R is lower alkyl, in the presence of an aliphatic alcohol having1 to 6 carbon atoms and an alkali metal as described in my applicationentitled Substituted 4'- 'Ihiazolidinones and Process Therefor,application Serial No. 93,301, filed concurrently herewith.

The starting materials for use in the preparation of the compounds ofthis invention are then prepared from these substituted4-thiazolidinones as follows:

wherein X is halogen, as described in my application entitledSubstituted 4-Thiazolidinones and Process Therewith.

The following examples are included in order further to illustrate thepresent invention:

EXAMPLE 1 Z-Carbethoxymetlzylene-3-Methyl-5-Brom0-4- T hiazolidinone Toa stirred solution of 20 g. (0.1 mole)Z-carbethoxymethylene-3-methyl-4-thiazolidinone in 120 ml. chloroform isadded, dropwise, a solution of 5 ml. (0.1 mole) bromine in 20 ml.chloroform. The solvent is removed by distillation and the residuecrystallized from methanol to yield 18 g. (65%) ofZ-carbethoxymethylene-3-methyl- 5-bromo-4-thiazolidinone, melting point76 C.

EXAMPLE 2 Z-Carbetlzoxymethylene-3-Methyl-5-Diethylamino-4-Thiaz0lidin0ne To a solution of 28 g. (0.1 mole)Z-carbethoxymethylcue-3methyl-5-bromo-4-thiazolidinone prepared asdescribed in Example 1 in 200 ml. benzene is added 14.5 g. (0.2 mole)diethylamine and the mixture is allowed to stand for 3 hours at 25 C.The resulting suspension is filtered to remove the precipitateddiethylamine hydrobromide and the filtrate is evaporated to dryness. Theresidue is taken up in ether, filtered and the filtrate saturated withdry hydrogen chloride to yield 25 g. (83%) of the hydrochloride salt of2-carbethoxymethylene-3-methyl- S-diethylamino-4thiazolidinone, meltingpoint 149-150 C., light-yellow crystals from absolute ethanol.

Analysis.Calc.: C, 46.67; H, 6.85; N, 9.07; S, 10.38; Cl, 11.47. Found:C, 46.75; H, 7.07; N, 9.13; S, 10.13; Cl, 11.82.

By a similar procedure, 2-carbethoxymethylene-3-methyl-5-bromo-4-thiazolidinone is reacted with other amines to preparethe following compounds:

EXAMPLE 3 Reaction with pyrrolidine yields Z-carbethoxymethylene-3-methyl-5-pyrrolidino4-thiazolidinone, melting point 123 C.

Analysis-Cale: C, 53.30; H, 6.71; N, 10.36; S, 11.86. Found: C, 53.30;H, 6.68; N, 10.45; S, 11.54.

EXAMPLE 4 Reaction with piperidine yields 2-carbethoxymethylene-3-methyl-5-piperidino-4thiazolidinone. Melting point of thehydrochloride salt is 158159 C.

Analysis (of the hydrchl0ride).--Calc.: C, 48.63; H, 6.59; N, 8.74; S,10.00; Cl, 11.05. Found: C, 48.77; H, 6.60; N, 8.72; S, 9.93; Cl. 10.79.

EXAMPLE Reaction with morpholine yields2-carbethoxymethylcue-3-methyl-S-morpholino-4-thiazolidinone, meltingpoint 153 C.

Analysis.Calc.: C, 50.32; H, 6.34; N, 9.78; S, 11.20. Found: C, 50.44;H, 6.33; N, 9.91; S, 10.98.

EXAMPLE 6 Reaction with 3-methylmorpholine yieldsZ-carbethoxymethylene-3-methyl-5-(3-methylmorpholino)-4 thiazolidinone,melting point 145 C.

Analysis.Calc.: C, 51.98; H, 6.72; N, 9.33; S. 10.67. Found: C, 52.15;H, 6.62; N, 9.40; S, 10.29.

It will be understood that the method of the present invention isadaptable to the preparation of compounds embraced by the formula:

other than those specifically enumerated in the foregoing examples. Forexample, other S-bromo derivatives may be used in the reaction, forexample Z-(a-carhomethoxyethylidene)-3-ethyl-5-bromo-4-thiazo1idinone,Z-(a-carbomethoxybenzylidene) -3-methyl-5-bromo-4-thiazolidinone,2-(wcarbethoxyethylidene)-3propyl-5-bromo4-thiazolidinone and the like,as Well as other amines, such as dimethylamine, dibutylamine,2-methylpiperidine, Z-methylpyrrolidine, 2-ethylpiperidine,3-ethylmorpholine, 2- methylmorpholine, 3-butylpyrrolidine and the like.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of my invention.

Having described my invention, what I desire to secure by Letters Patentis:

1. A compound of the formula:

wherein R is a member selected from the group consisting of hydrogen,lower alkyl and phenyl, R is lower alkyl and R is lower alkyl.

8. 2 carbethoxymethylene 3 methyl 5 bromo 4- thiazolidinone.

9. A method of preparing compounds of the formula:

wherein R is a member selected from the group consisting of hydrogen,lower alkyl and phenyl, R is lower alkyl and R is lower alkyl, whichcomprises treating a solution in an inert solvent of a compound of theformula:

with bromine.

10. A method according to claim 9 wherein said inert solvent ischloroform and the reaction is carried out at a temperature of about 25C.

11. A method of preparing compounds of the formula:

6. pyrrolidino, morpholino and mono-lower alkyl derivatives thereof,which comprises treating a solution in an inert solvent of a compound ofthe formula:

with an amine of the formula R -H.

12. A method according to claim 11 wherein said inert solvent is benzeneand the reaction is carried out at a temperature of about 25 C.

No references cited.

1. A COMPOUND OF THE FORMULA: